Overview. The Laboratory of Behavioral and Genomic Neuroscience continued a program of research in this year(October, 2015 to September, 2065) designed to develop mouse models of emotional disorders and addiction, with focus remaining on corticostriatal circuits. Individuals exposed to extreme forms of trauma and neglect are more prone to suffer from emotional disorders, such as anxiety and depression, that are comorbid with alcohol use disorders. It is far from clear exactly how alcohol abuse increases later risk for these neuropsychiatric disorders. Another unresolved question is why some individuals appear especially sensitive to effects of stress, while others are resilient. This inter-individual variation suggests that genetics play a significant role in modulating stress, a notion supported by recent research in humans. Unfortunately, there are inherent limitations to the study of genetic and environmental influences on behavior under tightly controled conditions in humans. Animal models provide a valuable alternative. The laboratory mouse potentially provides an excellent model system to study neural factors modulating behavior due to the availability of genetically-distinct mouse strains and the capacity for engineering genetic mutants. The Section on Behavioral Science and Genetics seeks to develop mouse models of cognitive abnormalities and alcohol use disorders. The laboratory was engaged in studies that addressed the goal of elucidating the role of to determine the effects of chronic alcohol on corticostriatal systems and their behavioral output. We employed a procedure of chronic intermittent EtOH (CIE) exposure via EtOH vapors. Our data show that CIE exposure produced marked structural and functional alterations in the same corticostriatal regions we had found in other studies to cognitive behavior. The marked structural and functional changes we observed in the DLS after CIE would support some role for DLS abnormalities. In order to test for effects of chronic EtOH on performance in the task, we exposed mice to CIE either prior to discrimination learning or before reversal. These experiments showed that CIE exposure produced a significant decrease in the number of errors made during either learning or relearning after reversal. Notably, CIE-induced facilitation of relearning was limited to the late stage of training, in a pattern of facilitation analogous to that we had earlier found after prefrontal cortex lesions. According to the scheme outlined above, this raises the possibility that enhanced reversal was caused by a CIE-induced functional lesion of the PL and a resultant loss of competition on stimulus-bound learning mediated by regions, including the DLS. However, it remains unclear at present whether these changes after CIE would necessarily results in gain, rather than loss, of a DLS contribution to performance. Further work is being undertaken to define the role of the DLS in order to better explain the behavioral effects of CIE. One major project examined the role of endocannabinoids as a mechanism underlying individual differences in fear extinction a form of inhibitory learning that aids recovery from psychological trauma. Working in collaboration with the laboratory of Dr. George Kunos, we tested the effects of a novel drug that boosts brain endocannabinoid levels (via prevention of degradation by the enzyme fatty acid amide hydrolase). Our work has found that either systemic or intra-amygdala delivery of this drug facilitates fear extinction in a mouse strain with impaired extinction. Supporting the amygdala as effect-locus, AM3506s extinction-facilitating effects were blocked by intra-amygdala CB1R antagonism and recapitulated by intra-amygdala AM3506. These findings reveal a new potential therapeutic approach to treating trauma. We are currently following this work up with studies on the precise mechanisms involved, with a focus on interactions with the amygdala serotonin system and the antidepressant drug, fluoxetine. Another major project tested the consequences of CIE for various behaviors including compulsive EtOH-seeking fear extinction. Our findings suggested a scheme whereby EtOH-induced loss of NMDAR-mediated cortical neuronal bursting disrupts encoding of extinction to impair the behavior. More generally, these observations provide novel evidence of how chronic EtOH disrupts corticoamygdala function, and predict that other behaviors dependent on this circuitry, such as compulsive drug-taking, will be adversely impacted by chronic EtOH. Clinically , our findings could have implications for understanding the neural basis of comorbid AUDs and anxiety. For example, loss of cortical modulation of extinction could impair recovery from psychological trauma and the efficacy of extinction-based therapies, increasing risk for anxiety disorders such as PTSD. Persistent anxiety could in turn foster further alcohol abuse, leading to a vicious cycle of abuse and progressively weakening prefrontal function. By the same token, treatments (e.g., endocannabinoid-targeting) that improve recovery from trauma could help break this cycle to reduce anxiety and alcohol abuse.